Selected recurrent genetic alterations in childhood B-ALL
| Genetic lesion . | Incidence in pediatric B-ALL, % . | Outcome . | Potential therapeutic implications . | Comments . |
|---|---|---|---|---|
| Aneuploidy | ||||
| Hyperdiploidy DNA Index >1.16 or >50 chromosomes | 20-25 | Favorable | Some consortia consider specific trisomies, +4 and +10 considered favorable by COG | |
| Hypodiploidy <44 chromosomes or DNA index <0.81 | 1-2 | Unfavorable; consideration of HSCT in first CR | Given common Ras pathway mutations; potential role for MEK or PI3K inhibitors | Worsening prognosis with fewer chromosomes; frequent TP53 mutations in low hypodiploid (32-39 chromosome); Ras pathway mutations common |
| Recurrent structural chromosomal aberrations | ||||
| t(12;21)(p13;q22) (cryptic); ETV6-RUNX1 fusion | 20-25 | Favorable | Less common with increasing age | |
| t(v;11)(v;q23) or t(11;v)(q23;v); KMT2A rearrangements | ∼3 noninfant B-ALL; >75 infant B-ALL | Unfavorable; noninfant improved with intensification of therapy; infant KMT2A-r dismal outcome regardless of therapy intensity | Hypomethylating agents;DOT1L inhibitors; Menin-KMT2A protein-protein interaction inhibitors;PRMT5 inhibitors; LSD1 inhibitors | KMT2A-AF4 most common fusion in B-ALL |
| +hsr(21)(q22); iAMP21 | 1-3 | Unfavorable; improved with intensification of therapy | ≥5 copies of RUNX1 | |
| t(17;19)(q22;p13); TCF3-HLF | <1 | Very poor | BCL2 inhibitor venetoclax | Associated with hypercalcemia and coagulopathy |
| t(1;19)(q23;p13); TCF3-PBX1 | 5 | Neutral with contemporary therapy | Poor outcome in older studies; higher incidence CNS disease and CNS relapse | |
| t(5;14)(q31;q32); IL3-IGH | 1-2 | Neutral | Associated with peripheral eosinophilia | |
| t(9;22)(q34;q11); BCR-ABL1 | ∼5 | Unfavorable with chemotherapy alone, greatly improved with TKI | ABL-targeting TKIs (eg, imatinib, dasatinib, etc.) | Incidence increases with age |
| Ph-like kinase fusions | ∼20 of HR B-ALL | Unfavorable | ABL class (ABL1, ABL2, PDGFRB, CSF1R rearranged): imatinib/dasatinib; JAK activating (CRLF2, JAK2, EPOR rearrangements; IL7R indels/mutations, SH3B deletion): Ruxolitinib, other JAK inhibitors; NTRK3 fusions: Crizotinib, Larotrectinib; PTK2B fusion: FAK inhibitor | Ongoing clinical trials investigating safety/efficacy of incorporation of TKIs into therapy |
| IGH-DUX4 | 3-7 | Favorable | Associated with dysregulation of ETS transcription factor, ERG; IKZF1 deletion common | |
| MEF2D rearranged (MEF2D-BCL9, MEF2D -HNRNPUL1, MEF2D-SS18, others) | 3-6 | Possibly unfavorable | Potential HDAC inhibitors | |
| ZNF384 rearranged (EP300-ZNF384, ARID1B-ZNF384, CREBBP-ZNF384, TCF3-ZNF384, others) | 3-5 | Neutral | Potential HDAC inhibitors | |
| Common molecular lesions | ||||
| IKZF1 deletion/mutation | 15 B-ALL;30 HR B-ALL;60-80 Ph+;50-60 Ph-like;30-40 DUX4/ERG dysregulated | Poor (except in DUX4/ERG dysregulated) | FAK inhibition plus TKI (if other ABL class lesion present);retinoic acid | Enriched at relapse; associated with glucocorticoid and TKI resistance |
| PAX5 deletions/mutations | ∼30 B-ALL | Neutral | ||
| TP53 mutations | ∼5 B-ALL; 10-20 of relapsed B-ALL; >90 low-hypodiploid B-ALL (32-39 chromosomes) | Poor | Somatic mutations enriched at relapse; >50% TP53 mutations in low-hypodiploid B-ALL are germ line; germ-line TP53 mutations associated with poor EFS/OS and increased risk for second malignancy | |
| NT5C2 mutations | 20 of relapsed B-ALL and T-ALL | Enzyme involved in nucleoside analog metabolism; gain of function mutations likely lead to decreased sensitivity to antimetabolite therapy | ||
| Ras pathway mutations | At diagnosis incidence varies by type of B-ALL; ∼50 of relapsed B-ALL | MEK inhibitors;PI3K inhibitors | ||
| CREBBP mutations | 20 of relapsed B-ALL | Associated with glucocorticoid resistance |
| Genetic lesion . | Incidence in pediatric B-ALL, % . | Outcome . | Potential therapeutic implications . | Comments . |
|---|---|---|---|---|
| Aneuploidy | ||||
| Hyperdiploidy DNA Index >1.16 or >50 chromosomes | 20-25 | Favorable | Some consortia consider specific trisomies, +4 and +10 considered favorable by COG | |
| Hypodiploidy <44 chromosomes or DNA index <0.81 | 1-2 | Unfavorable; consideration of HSCT in first CR | Given common Ras pathway mutations; potential role for MEK or PI3K inhibitors | Worsening prognosis with fewer chromosomes; frequent TP53 mutations in low hypodiploid (32-39 chromosome); Ras pathway mutations common |
| Recurrent structural chromosomal aberrations | ||||
| t(12;21)(p13;q22) (cryptic); ETV6-RUNX1 fusion | 20-25 | Favorable | Less common with increasing age | |
| t(v;11)(v;q23) or t(11;v)(q23;v); KMT2A rearrangements | ∼3 noninfant B-ALL; >75 infant B-ALL | Unfavorable; noninfant improved with intensification of therapy; infant KMT2A-r dismal outcome regardless of therapy intensity | Hypomethylating agents;DOT1L inhibitors; Menin-KMT2A protein-protein interaction inhibitors;PRMT5 inhibitors; LSD1 inhibitors | KMT2A-AF4 most common fusion in B-ALL |
| +hsr(21)(q22); iAMP21 | 1-3 | Unfavorable; improved with intensification of therapy | ≥5 copies of RUNX1 | |
| t(17;19)(q22;p13); TCF3-HLF | <1 | Very poor | BCL2 inhibitor venetoclax | Associated with hypercalcemia and coagulopathy |
| t(1;19)(q23;p13); TCF3-PBX1 | 5 | Neutral with contemporary therapy | Poor outcome in older studies; higher incidence CNS disease and CNS relapse | |
| t(5;14)(q31;q32); IL3-IGH | 1-2 | Neutral | Associated with peripheral eosinophilia | |
| t(9;22)(q34;q11); BCR-ABL1 | ∼5 | Unfavorable with chemotherapy alone, greatly improved with TKI | ABL-targeting TKIs (eg, imatinib, dasatinib, etc.) | Incidence increases with age |
| Ph-like kinase fusions | ∼20 of HR B-ALL | Unfavorable | ABL class (ABL1, ABL2, PDGFRB, CSF1R rearranged): imatinib/dasatinib; JAK activating (CRLF2, JAK2, EPOR rearrangements; IL7R indels/mutations, SH3B deletion): Ruxolitinib, other JAK inhibitors; NTRK3 fusions: Crizotinib, Larotrectinib; PTK2B fusion: FAK inhibitor | Ongoing clinical trials investigating safety/efficacy of incorporation of TKIs into therapy |
| IGH-DUX4 | 3-7 | Favorable | Associated with dysregulation of ETS transcription factor, ERG; IKZF1 deletion common | |
| MEF2D rearranged (MEF2D-BCL9, MEF2D -HNRNPUL1, MEF2D-SS18, others) | 3-6 | Possibly unfavorable | Potential HDAC inhibitors | |
| ZNF384 rearranged (EP300-ZNF384, ARID1B-ZNF384, CREBBP-ZNF384, TCF3-ZNF384, others) | 3-5 | Neutral | Potential HDAC inhibitors | |
| Common molecular lesions | ||||
| IKZF1 deletion/mutation | 15 B-ALL;30 HR B-ALL;60-80 Ph+;50-60 Ph-like;30-40 DUX4/ERG dysregulated | Poor (except in DUX4/ERG dysregulated) | FAK inhibition plus TKI (if other ABL class lesion present);retinoic acid | Enriched at relapse; associated with glucocorticoid and TKI resistance |
| PAX5 deletions/mutations | ∼30 B-ALL | Neutral | ||
| TP53 mutations | ∼5 B-ALL; 10-20 of relapsed B-ALL; >90 low-hypodiploid B-ALL (32-39 chromosomes) | Poor | Somatic mutations enriched at relapse; >50% TP53 mutations in low-hypodiploid B-ALL are germ line; germ-line TP53 mutations associated with poor EFS/OS and increased risk for second malignancy | |
| NT5C2 mutations | 20 of relapsed B-ALL and T-ALL | Enzyme involved in nucleoside analog metabolism; gain of function mutations likely lead to decreased sensitivity to antimetabolite therapy | ||
| Ras pathway mutations | At diagnosis incidence varies by type of B-ALL; ∼50 of relapsed B-ALL | MEK inhibitors;PI3K inhibitors | ||
| CREBBP mutations | 20 of relapsed B-ALL | Associated with glucocorticoid resistance |
CNS, central nervous system; COG, Children’s Oncology Group; CR, complete remission; EFS, event-free survival; ETS, erythroblast transforming specific; HDAC, histone deacetylase inhibitor; HR, high risk; HSCT, hematopoietic stem cell transplant; iAMP21, intrachromosomal amplification of chromosome 21; IL7R, interleukin-7 receptor; OS, overall survival; Ph+, Philadelphia chromosome; T-ALL, T-cell acute lymphoblastic leukemia; TKI, tyrosine kinase inhibitor.